Combivir - instructions for use, dose, side effects, contraindications

Component	Content (mg / tablet)
*Core tablet:*
Active substances:
Lamivudine	150,00
Zidovudine	300,00
Excipients:
Microcrystalline cellulose	269,62
Carboxymethyl starch of sodium, type A	22,50
Silica colloidal dioxide	2,25
Magnesium stearate	5,63
*Tablet casing:*
Ramp-white:	16.9-20.6 mg / tablet
- Hypromellose	59,75 %
- Titanium dioxide	31,25%
- Macrogol 400	8,00 %
- Polysorbate 80	1,00%

Description:The film-coated tablets are oval in shape, from white to almost white, with a risk on each side of the tablet and engraved with the inscription "GXFC3" on each side of the tablet.

Pharmacotherapeutic group:Antiviral (HIV) agent

ATX: & nbsp

J.05.A.R.01 Zidovudine + Lamivudine

Pharmacodynamics:

Mechanism of action

Zidovudine and lamivudine are potent selective inhibitors of HIV-1 and HIV-2. Both active substances are sequentially metabolized by intracellular kinases to 5'-triphosphates (TF). Zidovudine-TF and lamivudine-TF act as substrates and are competitive inhibitors of HIV reverse transcriptase. Their main antiviral effect is the ability to be built in the form of monophosphate into the viral DNA chain, leading to its breakage. Trisphosphates of zidovudine and lamivudine have a much lower affinity for DNA polymerases of the host cell.

No antagonistic effects were observed under conditions in vitro when using lamivudine and other antiretroviral drugs (tested substances: abacavir, didanosine, nevirapine, zalcitabine and zidovudine). Also there was no antagonistic effects in conditions in vitro when using zidovudine and other antiretroviral drugs (tested substances: abacavir, didanosine, lamivudine and interferon alfa).

In studies in vitro lamivudine has a weak cytotoxic effect on peripheral blood lymphocytes, as well as on lymphocytic and monocyte-macrophage cell lines and a number of other bone marrow precursor cells. In this way, lamivudine has a high therapeutic index in vitro.

Pharmacodynamic effects

Resistance of HIV-1 to lamivudine is due to a mutation M184V in a codon located close to the active center of viral reverse transcriptase (RT) of HIV. This mutation variant is observed both in conditions in vitro, and in HIV-1-infected patients who had antiretroviral therapy (Apt), including lamivudine. When mutating M184V the sensitivity to lamivudine is significantly reduced and the ability of the virus to replicate in vitro. In studies in vitro it has been established that zidovudine-resistant strains of the virus can become susceptible to its action if these strains develop resistance to lamivudine simultaneously.However, the clinical significance of such changes has not been fully established to date.

Mutation M184V in the codon of reverse transcriptase leads to the emergence of cross-resistance of HIV only for antiretroviral drugs from the class of nucleoside inhibitors. Zidovudine and stavudine remain active against HIV-1 strains resistant to lamivudine. Abacavir preserves antiretroviral activity against HIV-1 strains resistant to lamivudine, with only M184V mutation. In HIV strains with a mutation M184V in the codon of reverse transcriptase, no more than 4-fold decrease sensitivity to didanosine and zalcitabine; the clinical significance of these phenomena is not established.

Resistance to thymidine analogues (such as zidovudine) is well characterized and occurs due to the gradual accumulation of specific mutations in 6 codons (41, 67, 70, 210, 215 and 219) of HIV reverse transcriptase. The viruses acquire phenotypic resistance to thymidine analogues as a result of a combination of mutations in codons 41 and 215 or the accumulation of at least four of six mutations.These mutations do not in themselves cause high cross-resistance to other nucleosides, which subsequently allows the use of other registered reverse transcriptase inhibitors.

Two models of multiple drug resistance mutations, the first of which is characterized by mutations in the HIV reverse transcriptase at codons 62, 75, 77, 116 and 151, and a second generally comprises a mutation T69S in combination with the insertion of 6 pairs of nucleotides in the same position. These models lead to the development of phenotypic resistance to zidovudine, as well as to other registered nucleoside reverse transcriptase inhibitors (NRTIs). Any of these two mutation models of multiple nucleoside resistance significantly limits the options for future therapy.

In clinical trials, the use of lamivudine in combination with zidovudine led to a reduction in viral load of HIV-1 in the blood and an increase in the number Cd4 cells. Clinical evidence suggests that the use of lamivudine in combination with zidovudine as a single drug or as part of treatment regimens that include zidovudine, leads to a significant reduction in the risk of progression of HIV infection and mortality.

Monotherapy with zidovudine and lamivudine alone led to the emergence of clinical strains of HIV with reduced sensitivity to these drugs in vitro. The results of clinical studies showed that in patients who had not previously received antiretroviral therapy, combination therapy with zidovudine and lamivudine slowed the emergence of resistant to zidovudine strains.

Tests on the sensitivity of HIV to various antiretroviral drugs in vitro They were not standardized, therefore various methodological factors can influence their results. Evaluation of the relationship between the sensitivity of HIV to zidovudine and / or lamivudine in vitro and the clinical response to therapy is at the research stage.

Zidovudine and lamivudine have been widely used as components of combination antiretroviral therapy in combination with other antiretroviral drugs of the same class (nucleoside reverse transcriptase inhibitors) or preparations of other classes (protease inhibitors, non-nucleoside reverse transcriptase inhibitors,integrase inhibitors and fusion inhibitors).

It is shown that combined antiretroviral therapy, including lamivudine, is effective against strains of HIV with mutations M184V, as well as in patients who have not previously received antiretroviral therapy.

Pharmacokinetics:

Suction

Zidovudine and lamivudine well absorbed from the intestine. Absolute bioavailability of zidovudine and lamivudine in adults after oral administration is usually 60-70% and 80-85%, respectively.

In a bioequivalence study, a comparison of Combivir® and Epivir® preparations (film-coated tablets, 150 mg) and Retrovir® (film-coated tablets, 300 mg) was performed, and the effect of food on speed and degree of absorption was studied. The bioequivalence of Combivir® to Epivir® 150 mg and Retrovir® 300 mg, as a single tablets on an empty stomach, was demonstrated.

After using Combivir®, the maximum values of the concentration in the blood plasma (FROMmOh) zidovudine and lamivudine (confidence interval 95%) were 1.8 (1.5-2.2) μg / ml and 1.5 (1.3-1.8) μg / ml, respectively. Median (range) values tmax zidovudine and lamivudine were 0.50 (0.25-2.00) h and 0.75 (0.50-2.00) h, respectively. Degree of absorption (AUC) zidovudine and lamivudine and the values of the half-life after eating with food were similar to those after taking an empty stomach, although the rate of absorption (FROMmOh, tmax) was reduced. The findings indicate the possibility of using Combivir® regardless of food intake.

It is not expected that the taking of crushed tablets with a small amount of semi-solid food or liquid will affect the pharmacological properties of the preparation and, consequently, the clinical effect. These conclusions are based on the physico-chemical and pharmacokinetic characteristics of the active substances and the nature of the dissolution of the Combivir® tablets in vitro in water, provided that the patient grinds and immediately takes 100% of the ground tablets.

Distribution

Studies have shown that with intravenous administration, the average apparent volume of zidovudine and lamivudine distribution is 1.6 and 1.3 l / kg, respectively. Lamivudine characterized by a linear change in pharmacokinetic parameters in the entire range of therapeutic doses and is insignificantly bound to the main protein of the blood plasma by albumin (less than 36% of serum albumin in vitro). Zidovudine binds to plasma proteins by 34-38%. Thus, the interaction of zidovudine and lamivudine with other drugs through their displacement from the connection with plasma proteins is unlikely.

The available data indicate that zidovudine and lamivudine penetrate into the central nervous system (CNS) and enter the cerebrospinal fluid (CSF). The average ratio of zidovudine and lamivudine concentration in CSF to their concentration in Serum blood in 2-4 hours after oral administration is approximately 0.5 and 0.12, respectively. The true degree of penetration, as well as the connection with clinical efficacy, are unknown.

Metabolism

Lamivudine is almost not metabolized and is mainly excreted unchanged by the kidneys. Metabolic interactions for lamivudine are unlikely because of a slight metabolism in the liver (5-10%) and a low degree of binding to plasma proteins.

Zidovudine 5'-glucuronide is the main metabolite in both blood plasma and urine, with approximately 50-80 % the accepted dose of zidovudine is excreted by renal excretion.3'-amino-3'-deoxythymidine (AMT) has been identified as an zidovudine metabolite after intravenous administration.

Excretion

The half-life of lamivudine is 5-7 hours. The average systemic clearance of lamivudine is approximately 0.32 L / h / kg, most of it is renal clearance (more than 70%), carried out by active tubular secretion through the system of organic cation transport.

According to studies with intravenous administration of zidovudine, the mean terminal half-life in blood plasma is 1.1 hours, and the average systemic clearance is 1.6 l / h / kg. The renal clearance of zidovudine is 0.34 l / h / kg, indicating glomerular filtration and active tubular secretion by the kidneys.

Special patient groups

Elderly patients

The pharmacokinetics of zidovudine and lamivudine in patients older than 65 years have not been studied.

Children

In children older than 5-6 months, the pharmacokinetic index of zidovudine is similar to that of adults. Zidovudine is well absorbed from the intestine, when used in all the studied dosages in adults and children, its bioavailability is 60-74%, with an average of 65%.Maximum concentration in equilibrium state (Css_max) is 4.45 μmol / l (1.19 μg / ml) after taking zidovudine in the form of a solution at a dose of 120 mg / m² body surface area and 7,7 μmol / l (2.06 μg / ml) after taking zidovudine at a dose of 180 mg / m² body surface area. Application in a dose of 180 mg / m² four times a day in children led to systemic exposure (AUC24 = 40.0 h * μmol / L or 10.7 h * μg / ml), similar to that used at a dose of 200 mg six times a day in adults (40.7 h * μmol / L or 10.9 h * μg / ml).

In six HIV-infected children aged 2 to 13 years, the pharmacokinetics of zidovudine in the blood plasma after application at a dose of 120 mg / m² three times a day and after switching to a dose of 180 mg / m² twice a day. System exposure (per diem AUC and FROMmax) in blood plasma when using the dosing regimen twice a day was equivalent to exposure with the same total daily dose divided into three doses.

In general, the pharmacokinetics of lamivudine in children is similar to that of adults. However, absolute bioavailability (approximately 55-65%) was lower in children younger than 12 years. In addition, the values of systemic clearance were higher in young children and decreased as they matured, reaching values similar to those in adult patients by about 12 years.In connection with these differences, the recommended dose of lamivudine in children (aged 3 months to 12 years, with a body weight of 6 kg to 40 kg) is 8 mg / kg / day. At this dose an average AUC_0-12 in the range of approximately 3800-5300 ng * h / ml. Recent data suggest that exposure in children aged 2 to 6 years can be reduced by about 30% compared with other age groups. Currently, additional data are expected to support this conclusion; currently available data do not indicate a lower efficacy of lamivudine in this age group.

Patients with impaired renal function

In studies involving patients with impaired renal function, it was shown that if renal function is impaired, lamivudine excretion is impaired due to reduced renal clearance. Patients with creatinine clearance less than 50 ml / min need to reduce the dose of the drug. An increase in zidovudine concentrations in patients with severe renal dysfunction was also demonstrated.

Patients with impaired hepatic function

Limited data obtained from patients with cirrhosis indicate the possibility of accumulating zidovudine in patients with impaired hepatic function due to a decrease in glucuronidation.Patients with severe impairment of liver function may require a dose adjustment of zidovudine.

Pregnancy

Pregnancy does not affect the pharmacokinetics of zidovudine and lamivudine. Lamivudine is found in the blood serum of newborns at the same concentrations as in the blood serum of the mother and cord blood, which is consistent with the idea of a passive transfer of lamivudine through the hematoplacental barrier. The results of measuring zidovudine concentrations in blood plasma were similar to those obtained for lamivudine.

Indications:Treatment of HIV infection in adults and children weighing at least 14 kg in combination antiretroviral therapy.

Contraindications:

- Hypersensitivity to zidovudine, lamivudine or any other component of the drug;

- severe neutropenia (neutrophil count less than 0.75 x 10⁹/ l) or anemia (hemoglobin less than 7.5 g / dl or 4.65 mmol / l).

A drug with a fixed combination of Combivir® doses should not be used in the following situations, since dose correction is necessary in these cases. If you need to reduce the dose or cancel one of the components of the drug Combivir® (zidovudine or lamivudine) for the patient are available separate preparations of zidovudine and lamivudine,in the form of tablets or solution for oral administration (see section "Method of administration and dose"):

- impaired renal function with creatinine clearance less than 50 ml / min (for a given dosage form);

- severe degree of impaired liver function (for a given dosage form);

- children with a body weight of less than 14 kg (for this dosage form).

Pregnancy and lactation:

Fertility

Data on the effect of zidovudine and lamivudine on fertility in women are not available.

Zidovudine does not affect the number, morphology and motility of spermatozoa in men.

Pregnancy

As a rule, when deciding whether to use antiretroviral drugs to treat HIV infection in pregnant women and, as a consequence, to reduce the risk of vertical transmission of HIV infection, the newborn should take into account animal studies as well as clinical experience in pregnant women. In this case, the use of zidovudine in pregnant women with subsequent therapy of newborn infants showed a decrease in the level of HIV transmission from the mother to the fetus.

A large amount of data on the use of zidovudine or lamivudine in pregnant women does not indicate developmentcongenital pathology in the fetus (for each of the drugs - more than 3000 outcomes after exposure during application during the first trimester, of which more than 2000 outcomes after exposure with simultaneous use of both drugs). On the basis of the above data, it can be concluded that when Combivir® is used in humans, the risk of congenital pathologies is unlikely.

The active ingredients of the Combivir® preparation can inhibit the replication of cellular DNA. In an animal study, it was shown that zidovudine is a transplacental carcinogen. The clinical significance of this data is unknown.

For HIV-infected women with co-infection with the hepatitis virus who are being treated with a lamivudine-containing medication, such as Combivir®, in the case of pregnancy, the possibility of recurrence of hepatitis after discontinuation of lamivudine therapy should be considered.

Mitochondrial dysfunction

In studies in vitro and in vivo it has been demonstrated that nucleoside and nucleotide analogues are capable of causing damage to mitochondria of varying degrees. There have been reports of mitochondrial dysfunction in HIV-negative infants,exposed to the nucleoside analogues in utero and / or in the postpartum period.

Breastfeeding period

Zidovudine and lamivudine are excreted in breast milk in concentrations similar to those found in serum.

Based on the survey results of more than 200 pairs of "mother / child" who received therapy for HIV infection, lamivudine concentrations in the serum of the blood of infants who are breastfed from mothers treated with HIV is very low (<4% of the concentration in the maternal serum) and gradually decreases to undetectable levels when the infants 24 weeks of age. Data on the safety of lamivudine in children less than three months old are not available.

After a single dose of zidovudine 200 mg among HIV-infected women, the mean concentration of zidovudine in breast milk was similar to that of serum.

HIV-infected women under any circumstances is not recommended for breast-feeding in order to avoid transmission of HIV to the infant.

Dosing and Administration:

The drug Combivir® is taken orally, regardless of food intake.

Combivir® therapy should be initiated and controlled by a physician with experience in the treatment of HIV infection.

To ensure the accuracy of dosing, the tablet must be swallowed whole without cracking. For the treatment of patients who experience difficulty in swallowing, the tablets can be ground and added to a small amount of semi-solid food or liquid. All the resulting mixture must be taken orally immediately.

If you need to reduce the dose or cancel one of the components of Combivir® (zidovudine or lamivudine), you should use separate preparations of zidovudine and lamivudine.

Special patient groups

Adults and children with a body weight of at least 30 kg

The recommended dose of Combivir® is 1 tablet twice a day.

Children with body weight from 21 to 30 kg

The recommended dose of Combivir® - ½ pills in the morning and 1 whole tablet in the evening.

Children with body weight from 14 to 21 kg

The recommended dose of Combivir® is ½ tablets twice a day.

The dosage regimen for children with a weight of 14-30 kg is based primarily on pharmacokinetic modeling and is supported by data from clinical trials in which zidovudine and lamivudine as a monotherapy. It is possible to increase the concentration of zidovudine, therefore, careful monitoring of this group of patients should be carried out.

Children weighing less than 14 kg

The use of Combivir® in children with a body weight of less than 14 kg is contraindicated, since it is impossible to correct the doses taking into account the weight of the child.

In such patients, separate zidovudine and lamivudine should be used in accordance with the prescribed dose of these drugs.

Elderly patients

Specific data on the use of Combivir® in elderly people are not available, but for elderly patients, extreme care should be taken, taking into account age-related changes, such as renal dysfunction and hematological changes.

Patients with impaired renal function

Patients with creatinine clearance less than 50 ml / min require a dose adjustment for lamivudine, therefore, in these patients, the use of separate zidovudine and lamivudine is recommended.

Patients with impaired hepatic function

Limited data obtained from patients with cirrhosis indicate the possibility of cumulation of zidovudine in patients with impaired liver function due to a decrease in the rate of formation of glucuronide.Data obtained using lamivudine in patients with impaired liver function moderate and severe would indicate that the liver has no significant effect on the pharmacokinetics of lamivudine. Nevertheless, it may be necessary to dose adjustment of AZT, however in patients with impaired liver function severe recommended to use separate preparations of zidovudine and lamivudine. The attending physicians should refer to the instructions for medical use for these medications.

Patients with hematologic adverse reactions

When the hemoglobin concentration is lower than 9 g / dL (5.59 mmol / L) or with neutropenia (the number of neutrophils is less than 1.0 ^x 10^d/ l), a dose adjustment of zidovudine may be required. Since correction of the dose of Combivir® is not possible, separate preparations of zidovudine and lamivudine should be used.

Side effects:

Adverse reactions have been described in the treatment of patients with HIV zidovudine and lamivudine in monotherapy or in combination. For many unwanted reactions, it remains unclear whether their occurrence is associated with zidovudine,lamivudine or other medications used to treat HIV infection, or they are the result of a major disease. Since the Combivir® formulation includes zidovudine and lamivudine, one can expect the appearance of the undesirable reactions of the indicated type and severity associated with each of these components described below. Currently, there is no evidence that the combination of zidovudine and lamivudine has increased toxicity.

There are reports of the development of lactic acidosis, including fatal, usually accompanied by severe hepatomegaly with steatosis, during therapy with zidovudine.

Treatment with zidovudine was accompanied by loss of subcutaneous fat, which was most pronounced in the face, limbs and buttocks. During therapy with Combivir®, patients should be screened regularly for signs of lipoatrophy, and if Combivir® is suspected of developing lipoatrophy, therapy with Combivir® should be discontinued.

Body weight and serum lipid and blood glucose concentrations may increase during antiretroviral therapy.

In HIV-infected patients with severe immunodeficiency at the time of the onset of combined antiretroviral therapy, an inflammatory response may occur against a background of asymptomatic opportunistic infections or their residual effects. There have also been cases of autoimmune diseases (for example, Graves' disease) on the background of restoration of immunity, but the time of primary manifestations varied and the disease could occur many months after the initiation of therapy.

Osteonecrosis cases have been reported, especially in patients with recognized risk factors, advanced HIV infection, or long-term combined Apt. The frequency of occurrence of this phenomenon is unknown.

Undesirable reactions assessed as related or possibly associated with Combivir® therapy are listed below in accordance with organ and organ damage and frequency of occurrence. Frequency of occurrence is defined as follows: Often (≥ 1/10), often (≥ 1/100 and <1/10), infrequently (≥ 1/1 000 and <1/100), rarely (≥ 1/10 000 and <1/1 000), rarely (<1/10 000, including individual cases). AT Within each category of frequency, adverse reactions are presented in descending order of severity.

Lamivudine

Violations of the blood and lymphatic system

Infrequently: neutropenia and anemia (sometimes severe), thrombocytopenia.

Rarely: true erythrocyte aplasia.

Disorders from the metabolism and nutrition

Often: hyperlactatemia.

Rarely: lactic acidosis.

Disturbances from the nervous system

Often: headache, insomnia.

Rarely: peripheral neuropathy (or paresthesia).

Disturbances from the respiratory system, chest and mediastinal organs

Often: cough, nasal symptoms.

Disorders from the gastrointestinal tract

Often: nausea, vomiting, abdominal pain or colic, diarrhea.

Rarely: pancreatitis, increased serum amylase activity.

Disturbances from the liver and bile ducts

Infrequently: transient increase in hepatic enzyme activity alanine aminotransferase (ALT), aspartate aminotransferase (ACT).

Rarely: hepatitis.

Disturbances from the skin and subcutaneous tissues

Often: rash, alopecia.

Rarely: angioedema.

Disturbances from musculoskeletal and connective tissue

Often: arthralgia, muscle disorders.

Rarely: rhabdomyolysis.

General disorders and disorders at the site of administration

Often: fatigue, general malaise, fever.

Zidovudine

The profile of adverse reactions is not different in adults and adolescents. The most serious adverse reactions are anemia (which may require blood transfusion), neutropenia and leukopenia. The listed adverse reactions are more likely to occur with higher doses of zidovudine (1200-1500 mg per day) and patients at advanced stages of HIV infection (especially with a reduced bone marrow reserve prior to treatment), particularly in patients with a number of cells Cd4 less than 100 / mm³. In some patients, it may be necessary to reduce the dose of zidovudine or to abolish it. Neutropenia occurs more often in patients who have a neutrophil count, hemoglobin concentration, and vitamin B concentration₁₂ in the blood serum reduced at the time of initiation of zidovudine treatment.

Violations of the blood and lymphatic system

Often: anemia, neutropenia and leukopenia.

Infrequently: thrombocytopenia and pancytopenia (with bone marrow hypoplasia).

Rarely: true erythrocyte aplasia.

Rarely: aplastic anemia.

Disorders from the metabolism and nutrition

Often: hyperlactatemia.

Rarely: lactoacidosis in the absence of hypoxemia, anorexia.

Disorders of the psyche

Rarely: anxiety and depression.

Disturbances from the nervous system

Often: headache.

Often: dizziness.

Rarely: insomnia, paresthesia, drowsiness, decreased mental activity, convulsions.

Heart Disease

Rarely: cardiomyopathy.

Disturbances from the respiratory, thoracic and mediastinal systems Infrequent: dyspnea.

Rarely: cough.

Disorders from the gastrointestinal tract

Often: nausea.

Often: vomiting, abdominal pain and diarrhea.

Infrequently: flatulence.

Rarely: pigmentation of the oral mucosa, perversion of taste, dyspepsia, pancreatitis.

Disturbances from the liver and bile ducts

Often: increase in blood activity of liver enzymes and concentration bilirubin.

Rarely: liver damage, such as severe hepatomegaly with steatosis.

Disturbances from the skin and subcutaneous tissues

Infrequently: rash and itching.

Rarely: pigmentation of nails and skin, hives and sweating.

Disturbances from musculoskeletal and connective tissue

Often: myalgia.

Infrequently: myopathy.

Disorders from the kidneys and urinary tract

Rarely: frequent urination.

Violations of the genitals and mammary gland

Rarely: gynecomastia.

General disorders and disorders at the site of administration

Often: general malaise.

Infrequently: fever, generalized pain syndrome and asthenia.

Rarely: chills, chest pain and flu-like syndrome.

Data from two clinical trials (placebo-controlled and open) indicate that the incidence of nausea and other frequently occurring clinical adverse events steadily declines during the first few weeks of zidovudine treatment.

Overdose:

Symptoms

Information about cases of overdose with Combivir® is limited. No specific symptoms or signs of an acute overdose of lamivudine or zidovudine have been identified, except for those listed in the "Side effect" section. None of the reported cases were fatal, the condition of all patients was normalized.

Treatment

In case of an overdose, the patient should be under the supervision of a physician in order to identify signs of a toxic effect of the drug, if necessary, conduct a standard maintenance therapy. Because the lamivudine is derived by dialysis, continuous hemodialysis can be used to treat an overdose, however, no studies have been conducted to evaluate the use of this method. It has been established that hemodialysis and peritoneal dialysis are ineffective for excretion of zidovudine, but accelerate the excretion of its glucuronide metabolite. The treating doctors are recommended refer to the instructions for the use of individual zidovudine and lamivudine preparations for more detailed data.

Interaction:

Because Combivir® contains zidovudine and lamivudine, it can enter into any interactions that are specific to each of these components separately. Clinical studies have not shown clinically significant interactions between zidovudine and lamivudine.

Zidovudine is mainly metabolized by uridine diphosphate-glucuronyltransferase (UDF-GT) enzymes; joint application of inducers or enzyme inhibitorsUDF-GT can affect the exposure of zidovudine. Lamivudine is excreted from the body by the kidneys. Active renal secretion of lamivudine in urine occurs through the system of transport of organic cations (OCT). The simultaneous use of lamivudine with OCT inhibitors or nephrotoxic drugs may increase the exposure of lamivudine.

Zidovudine and lamivudine are not significantly metabolized by cytochrome P450 enzymes (eg, CYP 3A4, CYP 2C9 or CYP 2D6) nor do they inhibit or induce this enzyme system. Thus, the interaction of zidovudine and lamivudine with protease inhibitors, non-nucleoside reverse transcriptase inhibitors and other antiretroviral drugs that are metabolized by the basic enzymes P450 is unlikely.

Studies of drug interactions were conducted only with the participation of adult patients. The list of interactions listed below should not be considered exhaustive, but it reflects the classes of drugs that should be used with caution.

Medicinal preparations by fields of application	Interaction Average geometric change (%) (possible mechanism)	Recommendations for joint application
ANTIRETROVIRAL DRUGS
Didanosine + 3TC	The interaction has not been studied.	No dose adjustment is required.
Didanosine + zidovudine	The interaction has not been studied.	No dose adjustment is required.
Stavudine + 3TC	The interaction has not been studied.	Joint use is not recommended.
Stavudine + zidovudine	In vitro antagonism of activity against HIV between stavudine and zidovudine may lead to a decrease in the effectiveness of both drugs.	Joint use is not recommended.
ANTI-INFECTIONAL PREPARATIONS
Atovahon + lamivudine	The interaction has not been studied.	Since limited data are available, the clinical significance is unknown.
Atovahon + zidovudine (750 mg twice daily during meals + 200 mg three times a day)	Zidovudine: AUC ↑ 33% Atovahon: AUC ↔
Clarithromycin + 3TC	The interaction has not been studied.	The interval between taking Combivir® and clarithromycin should be at least 2 h.
Clarithromycin + zidovudine (500 mg twice daily + 100 mg every 4 hours)	Zidovudine: AUC ↓ 12%
Trimethoprim + sulfamethoxazole (co-trimoxazole) + lamivudine (160 mg + 800 mg once daily for 5 days + 300 mg once)	Lamivudine: AUC ↑ 40% Trimethoprim: AUC ↔ Sulfamethoxazole: AUC ↔ (inhibition of the organic cation transport system)	With the exception of patients with impaired renal function, dose adjustment of Combivir® is not required. If simultaneous use of co-trimoxazole is warranted, patients should be under clinical supervision. Joint application with high doses of trimethoprim + sulfamethoxazole for the treatment of pneumonia caused by Pneumocystis jirovecii (R. carinii), and toxoplasmosis, has not been studied, and should be avoided.
Trimethoprim + sulfamethoxazole (co-trimoxazole) + zidovudine	The interaction has not been studied.
Antihypertensive drugs
Fluconazole + 3TC	The interaction has not been studied.	Since limited data are available, the clinical significance is unknown. It is necessary to monitor the signs of zidovudine toxicity.
Fluconazole + zidovudine (400 mg once a day + 200 mg three times a day)	Zidovudine: AUC ↑ 74% (inhibition of UDP-HT)
ANTIMICOBACTERIAL PREPARATIONS
Rifampicin + 3TC	The interaction has not been studied.	There is not enough data to recommend a dose adjustment
Rifampicin + zidovudine (600 mg once a day + 200 mg three times a day)	Zidovudine: AUC ↓ 48% (induction of UDF-HT)	There is not enough data to recommend a dose adjustment
ANTI-TREATMENT PREPARATIONS
Phenobarbital + 3TC	The interaction has not been studied.	There is not enough data to recommend a dose adjustment.
Phenobarbital + zidovudine	The interaction has not been studied. There may be a slight decrease in zidovudine concentration in the blood plasma by inducing UDF-HT.	There is not enough data to recommend a dose adjustment.
Phenytoin + lamivudine	The interaction has not been studied.	It is necessary to control the concentration of phenytoin.
Phenytoin + zidovudine	Phenytoin: AUC ↑ ↓	It is necessary to control the concentration of phenytoin.
Valproic acid + 3TC	The interaction has not been studied.	Since limited data are available, the clinical significance is unknown. It is necessary to monitor the signs of zidovudine toxicity.
Valproic acid + zidovudine (250 mg or 500 mg three times a day + 100 mg three times a day)	Zidovudine: AUC ↑ 80% (inhibition of UDP-HT)
BLOCKERS OF H2-HISTAMIN RECEPTORS
Ranitidine + lamivudine	The interaction has not been studied. Clinically significant interaction is unlikely. Ranitidine partially excreted by active tubular secretion through the system of transport of organic cations.	No dose adjustment is required.
Ranitidine + zidovudine	The interaction has not been studied.	No dose adjustment is required.
Cimetidine + 3TC	The interaction has not been studied. Clinically significant interaction is unlikely. Cimetidine partially excreted by active tubular secretion through the system of transport of organic cations.	No dose adjustment is required.
Cimetidine + zidovudine	The interaction has not been studied.	No dose adjustment is required.
CYTOTOXIC PREPARATIONS
Cladribine + 3TC	The interaction has not been studied. In vitro lamivudine inhibits intracellular phosphorylation of cladribine, leading to a possible risk of loss of cladribine efficacy in the case of a combination in clinical practice. Some clinical data also confirm the possible interaction between lamivudine and cladribine.	Thus, the combined use of lamivudine and cladribine is not recommended.
OPIOID PREPARATIONS
Methadone + 3TC	The interaction has not been studied.	Since limited data are available, the clinical significance is unknown. It is necessary to monitor the signs of zidovudine toxicity. In most cases, the need for correcting the dose of methadone is unlikely, but sometimes it may be necessary to titrate the dose again.
Methadone + zidovudine (from 30 to 90 mg once a day + 200 mg every 4 hours)	Zidovudine: AUC ↑ 43% Methadone: AUC ↔
URINOZURIC PREPARATIONS
Probenecid + 3TC	The interaction has not been studied.	Since limited data are available, the clinical significance is unknown. It is necessary to monitor the signs of zidovudine toxicity.
Probenecid + zidovudine (500 mg four times a day + 2 mg / kg three times a day)	Zidovudine: AUC ↑ 106% (inhibition of UDP-HT)

Abbreviations: ↑ = increase in the indicator; ↓ = decrease in the indicator; ↔ = no significant changes; AUC = area under the concentration-time curve.

Emtricitabine

Lamivudine can suppress intracellular phosphorylation of emtricitabine while simultaneously using these drugs. In addition, the mechanism of viral resistance to lamivudine and emtricitabine is mediated by a mutation of the same viral reverse transcriptase gene (M184V), so the therapeutic efficacy of these drugs in combination therapy may be limited. The use of lamivudine in combination with emtricitabine or combinations of fixed doses containing emtricitabine, Not recommended.

Lamivudine

Simultaneous use of zidovudine and lamivudine leads to an increase in zidovudine exposure by 13% and an increase in its maximum plasma concentration by 28%. However, the total exposure of zidovudine (AUC) does not change significantly. Zidovudine does not affect the pharmacokinetics of lamivudine.

Other drugs

There have been reported cases of exacerbation of anemia associated with the use of ribavirin, when zidovudine was part of the HIV treatment regimen, but the exact mechanism is currently unknown. The simultaneous use of ribavirin and zidovudine is not recommended due to an increased risk of anemia.

In the case of a combined APT scheme containing zidovudine, the possibility of zidovudine replacement should be considered. This is especially important for patients with a history of anemia caused by zidovudine.

Concomitant treatment, especially intensive therapy, with potentially nephrotoxic or myelosuppressive drugs (such as: pentamidine for systemic use, dapsone, pyrimethamine, co-trimoxazole, amphotericin, flucytosine, ganciclovir, interferon, vincristine, vinblastine and doxorubicin) may also increase the risk of developing unwanted reactions to zidovudine. In case of concomitant use of Combivir® and any of the listed medicines, careful monitoring of kidney function and hematological parameters is required. If necessary, reduce the dose of one or more drugs.

Limited data from clinical trials do not indicate a significant increase in the risk of adverse reactions to zidovudine with simultaneous application with co-trimoxazole (see above information on the interaction of lamivudine and co-trimoxazole), pentamidine in the form of aerosol, pyrimethamine and acyclovir in preventive doses.

Special instructions:

The following are special guidelines for zidovudine and lamivudine. There are no additional specific indications related to the Combivir® preparation.

If it is necessary to adjust the dose, it is recommended to use separate preparations of zidovudine and lamivudine.In such cases, the treating physician should refer to separate instructions for use for these medicines.

Patients should be warned about the possible consequences of concurrent use of other medications without prescribing a doctor.

Although it has been proved that effective suppression of the virus with antiretroviral therapy significantly reduces the risk of transmission of HIV to other people during sexual intercourse, it is impossible to exclude this risk completely. Patients should take precautions to prevent HIV transmission in accordance with national guidelines.

You should avoid the simultaneous use of stavudine and zidovudine.

Combivir® should not be used concomitantly with medications containing lamivudine or emtricitabine.

Simultaneous reception of lamivudine and cladribine is not recommended.

Opportunistic infections

The use of Combivir® or any other antiretroviral drugs does not preclude the development of opportunistic infections or other complications of HIV infection, so patients should remain under close clinical supervision of physicians with experience in HIV treatment.

Hematologic disorders

In patients receiving zidovudine treatment, one can expect the development of anemia, neutropenia and leukopenia (usually secondary to neutropenia). Most often, these phenomena develop with higher doses of zidovudine (1200-1500 mg / day), in patients with late stage of HIV infection and in patients with a reduced bone marrow reserve before treatment. Therefore, patients taking Combivir® should carefully monitor hematologic parameters.

These hematologic abnormalities usually occur no earlier than 4-6 weeks after initiation of therapy. For patients with advanced HIV infection with symptoms, a blood test is recommended at least every two weeks during the first three months of therapy and at least once a month. In patients with early stage of HIV infection, unwanted reactions from the blood are infrequent. Depending on the general condition of the patient, the blood test can be performed less often, for example, every 1-3 months.

With the development of severe anemia or myelosuppression during treatment with Combivir®,as well as in patients with an existing bone marrow impairment, for example, with a hemoglobin concentration of less than 9 g / dl (5.59 mmol / L) or a neutrophil count of less than 1.0 x 10⁹/ l, zidovudine dose adjustment may also be required. Since Combivir® is not available for dose adjustment, these patients should be prescribed zidovudine and lamivudine in the form of separate preparations.

For more information, refer to the instructions for the use of certain zidovudine and lamivudine.

Pancreatitis

In patients treated with zidovudine and lamivudine, rare cases of pancreatitis have been reported, but it is unclear whether these cases are due to antiretroviral therapy or are a consequence of HIV infection. If there are clinical signs, symptoms or changes in laboratory indicators suggesting the possibility of developing pancreatitis, then immediately stop taking Combivir®.

Lactic acidosis

When zidovudine was used, cases of lactic acidosis, usually with hepatomegaly and steatosis of the liver, were reported.Early symptoms (symptomatic hyperlactatemia) include minor symptoms on the part of the digestive system (nausea, vomiting and abdominal pain), nonspecific general malaise, loss of appetite, weight loss, respiratory symptoms (rapid and / or deep breathing), or neurologic symptoms (including including motor weakness).

Lactic acidosis is characterized by high mortality and can develop against a background of pancreatitis, liver failure or renal insufficiency.

Lactic acidosis usually develops after several months of treatment.

Combivir® treatment should be discontinued if symptomatic hyperlactatemia and metabolic acidosis / lactic acidosis develop, progressive hepatomegaly, or a rapid increase in aminotransferase activity.

Caution should be exercised when combivir® is used to treat any patient (especially obese women) with hepatomegaly, hepatitis, or other known risk factors for liver damage and steatosis of the liver (including the use of certain drugs and alcohol use).

Patients with co-infection with hepatitis C virus who are treated with interferon alpha and ribavirin can be a special risk group.

Patients of the special risk group should be closely monitored.

Lipoatrophy

Treatment with zidovudine was accompanied by loss of subcutaneous fat. The incidence and severity of lipoatrophy are related to the total exposure of the drug. Such a loss of fat, which is most pronounced in the face, limbs and buttocks, can only be reversed, and the improvement can only come a few months after switching to a treatment regimen that does not contain zidovudine. During therapy with zidovudine and other drugs containing zidovudine, patients should be regularly monitored for signs of lipoatrophy, and if suspected of developing lipoatrophy, an alternative regimen should be taken if possible.

Body weight and metabolic parameters

During antiretroviral therapy, there may be an increase in body weight, an increase in the concentration of lipids and blood glucose.Control of the disease and lifestyle changes can also contribute to this process. In some cases, data have been obtained that indicate a link between increased lipid concentrations and therapy, but there is no strong evidence for a relationship between weight gain and any specific therapy. Determination of lipid and blood glucose concentrations should be carried out in accordance with established guidelines for HIV treatment. Disorders of lipid metabolism should be adjusted in accordance with clinical manifestations.

Immunodeficiency Syndrome

In HIV-infected patients with severe immunodeficiency, the onset of antiretroviral therapy (APT) may lead to the development of an inflammatory response in response to activation of pathogens of asymptomatic or residual opportunistic infections, which can lead to serious deterioration or worsening of symptoms. Typically, these reactions occur within the first few weeks or months after the onset of APT. Typical examples are cytomegalovirus retinitis, generalized and / or focal infection caused by mycobacteria, and pneumonia caused by Pneumocystis jirovecii (R. carinii). The appearance of any symptoms of inflammation requires immediate examination and, if necessary, treatment.

Autoimmune diseases (eg, Graves' disease, polymyositis and Guillain-Barre syndrome) were also observed against the background of restoration of immunity, but the time of primary manifestations varied, and the disease could occur many months after initiation of therapy and sometimes had an atypical course.

Diseases of the liver

If lamivudine is used simultaneously for the treatment of HIV infection and hepatitis B virus infection (HBV), additional information on the use of lamivudine for the treatment of hepatitis B infection is available in the medical instructions for lamivudine preparations at a dosage of 100 mg.

The efficacy and safety of Combivir® have not been established in patients with severe concomitant liver disease.

Patients with concomitant chronic hepatitis B or C receiving combination antiretroviral therapy have an increased risk of developing severe and potentially lethal adverse reactions from the liver.In the case of concomitant antiviral therapy for hepatitis B or C, you should also read the relevant instructions for the use of these medications.

When discontinuing the use of Combivir® in patients with co-infection with hepatitis B virus, periodic monitoring of liver function and hepatitis B replication markers is recommended for 4 months, as stopping lamivudine may exacerbate hepatitis.

In patients with an existing impairment of liver function, including active chronic hepatitis, there is an increase in the incidence of liver dysfunction during combined antiretroviral therapy. Such patients should be monitored in accordance with standard clinical practice. It is necessary to consider the possibility of suspending or stopping treatment in cases of manifestations of worsening liver disease in such patients.

Concomitant viral hepatitis C

It is not recommended simultaneous use of zidovudine and ribavirin because of the increased risk of anemia.

Mitochondrial dysfunction due to intrauterine exposure

Analogues of nucleosides and nucleotides are able to influence the mitochondrial function to a varying degree, which is most clearly manifested when stavudine, didanosine and zidovudine are used; mainly this refers to treatment regimens including zidovudine. The main undesirable reactions were hematologic disorders (anemia, neutropenia) and metabolic disorders (hyperlactatemia, hyperlipazemia). These undesirable reactions, as a rule, were transient. Rare neurological disorders with late onset are recorded (hypertension, convulsions, behavioral disorders). Whether these neurological disorders are transient or permanent, is currently unknown. The probability of mitochondrial dysfunction should be considered in any child exposed to intrauterine exposure to nucleoside and nucleotide analogues, with marked clinical symptoms of unclear etiology, in particular neurological disorders. The presented data do not influence the current national recommendations on the use of antiretroviral therapy in pregnant women for the prevention of vertical transmission of HIV infection.

Osteonecrosis

Despite the fact that the etiology of this disease is multifactorial (including the use of corticosteroids, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis of the most frequently observed in patients with advanced HIV infection and / or long-receiving combination antiretroviral therapy. Patients should consult a doctor if they experience pain and joint stiffness or difficulty in moving.

Effect on the ability to drive transp. cf. and fur:Special studies to evaluate the effect of zidovudine and lamivudine on the ability to drive vehicles and work with mechanisms have not been conducted. Pharmacological properties of active substances do not allow to predict the effect of Combivir® on these activities. However, when assessing a patient's ability to drive vehicles and operate machinery should take into account his clinical condition and the profile of adverse reactions of the drug Combivir ™.

Form release / dosage:Tablets, film-coated, 300 mg + 150 mg.

Packaging:10 tablets in AlPVC Blister.For 6 blisters together with instructions for medical use put in a cardboard box.

Storage conditions:

2 years.

Do not use after the expiration date stated on the package.

Shelf life:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children.

Terms of leave from pharmacies:On prescription

Registration number:П N016050 / 01

Date of registration:13.11.2009 / 31.05.2016

Expiration Date:Unlimited

The owner of the registration certificate:VeeV Helsker United Kingdom LimitedVeeV Helsker United Kingdom Limited United Kingdom

Manufacturer: & nbsp

GLAXO OPERATIONS UK, Limited United Kingdom

GlaxoSmithKline Pharmaceuticals, S.A. Poland

BINNOFARM, CJSC Russia

Representation: & nbspGlaxoSmithKline Trading, ZAOGlaxoSmithKline Trading, ZAO

Information update date: & nbsp25.09.2017

Illustrated instructions

Instructions

Combivir® (Combivir®)